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viruses
Review
Mechanisms of Hepatocellular Injury in Hepatitis A
Minghang Wang 1 and Zongdi Feng 1,2, *
1 Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital,
Columbus, OH 43205, USA; minghang.wang@nationwidechildrens.org
2 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
* Correspondence: zongdi.feng@nationwidechildrens.org
Abstract: Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide.
Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely un-
derstood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been
that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence
suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute
to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has
been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic
variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP)
have been linked to hepatitis A severity. This review summarizes the current knowledge of the
mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under
different conditions and they are not necessarily mutually exclusive. A better understanding of these
mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.
Keywords: hepatitis A virus; liver injury; bystander T cell activation; MAVS signaling; TIM-1
polymorphism; IL-18BP deficiency
Citation: Wang, M.; Feng, Z.
Mechanisms of Hepatocellular Injury 1. Introduction
in Hepatitis A. Viruses 2021, 13, 861. Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis world-
https://doi.org/10.3390/v13050861 wide. HAV is transmitted via a fecal–oral route and is most prevalent in resource-poor
countries where transmission via contaminated food or water often causes point source
Academic Editor: Albert Bosch outbreaks [1]. HAV infection is usually self-limited, but can cause debilitating disease
and even death [2]. Despite the existence of highly effective vaccines, an estimated
Received: 5 April 2021
47 million infections occurred in 2010, resulting in 94,000 deaths [3]. Although outbreaks in
Accepted: 6 May 2021
industrialized countries are relatively uncommon, the most recent outbreak of hepatitis
Published: 8 May 2021
A in the United States started in 2016, involved 35 states, and signaled the re-emergence
of hepatitis A. As of April 16, 2021, there are 38,795 publicly reported cases, resulting in
Publisher’s Note: MDPI stays neutral
23,585 hospitalizations (61%) and 372 deaths (https://www.cdc.gov/hepatitis/outbreaks/
with regard to jurisdictional claims in
2017March-HepatitisA.htm, accessed on 1 April 2021).
published maps and institutional affil-
After fecal–oral transmission of HAV, the virus enters the blood stream via a poorly
iations.
understood process to gain access to the liver, the target organ, for its propagation. Acute
HAV infection is associated with a lengthy incubation period (4–6 weeks), during which
large amounts of virus are shed into the feces [1]. The virus is detected in the blood (viremia)
for several weeks before and after the onset of clinical symptoms. During the peak of virus
Copyright: © 2021 by the authors.
shedding, most patients produce HAV-specific IgM, followed by IgG. The appearance of
Licensee MDPI, Basel, Switzerland.
anti-HAV IgM coincides with elevated liver enzymes [Alanine aminotransferase (ALT) and
This article is an open access article
aspartate aminotransferase (AST)] in the serum, a hallmark of liver damage. Cytotoxic T
distributed under the terms and
cells are detected in the acute phase and early convalescent phase and play a pivotal role in
conditions of the Creative Commons
viral clearance [4].
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
HAV is a small RNA virus belonging to the Picornaviridae family. Unlike many other
4.0/).
picornaviruses, HAV replicates very slowly and does not cause apparent cytopathic effects
Viruses 2021, 13, 861. https://doi.org/10.3390/v13050861 https://www.mdpi.com/journal/virusesViruses 2021, 13, 861 2 of 9
in cell culture [5]. This is in line with a relatively long incubation period of acute HAV
infection in humans [1,4]. Our recent work has shown that HAV usurps the cellular endo-
somal sorting complex to exit as membrane-cloaked, quasi-enveloped particles (eHAV),
providing a long-sought explanation for noncytolytic release and spread of HAV [6]. The
eHAV particles are the only virion form detected in patient serum, thus they most likely
mediate the virus spread to the liver [7].
Studying HAV pathogensis in patients has been difficult due to limited access to
patient samples. Several species of non-human primates (NHPs), including mamosets,
owl monkeys, and chimpanzees, are susceptible to HAV and produce diseases similar
to those in humans, therefore have been used for studying the pathogenesis associated
with HAV infection [8,9]. More recently, a murine model was established by Lemon and
colleagues [10]. Studies in these animal models have provided insights into the pathogensis
of HAV infection in humans.
2. Clinical Features of Hepatitis A
Symptoms associated with hepatitis A are clinically indistinguishable from those of
other types of viral hepatitis. Typically, HAV infection results in acute viral hepatitis charac-
terized by fatigue, fever, nausea, vomiting, anorexia, abdominal pain, and jaundice [11,12].
ALT and AST concentrations in patient serum are considered sensitive indicators of hep-
atocellular injury [13], providing reliable quantitative measures of liver damage. Unlike
other forms of viral hepatitis, hepatitis A has no documented chronic cases. The clinical
outcomes of hepatitis A are generally variable, ranging from asymptomatic to fulminant
hepatitis [11,14]. In general, children with hepatitis A experience a much milder clinical
course than adults; about 70% of HAV infection in children are asymptomatic, while symp-
tomatic infection rates in adults are estimated to be higher than 70% [15,16]. Fulminant
hepatitis, an unusual complication of hepatitis A, is considered a significant contributor to
death in patients [17].
Hepatitis A has multiple atypical manifestations, including relapsing hepatitis,
cholestatic hepatitis, and extrahepatic manifestations [18–20]. Relapsing hepatitis usually
occurs 4 to 15 weeks following acute viral hepatitis. A much milder clinical development in
the relapsing phase of hepatitis A is generally observed than in the initial infection [21,22].
However, patients may experience more than one relapsing course of hepatitis A [22]. The
mechanism underlying the recurrence of hepatitis A remains poorly understood. HAV-
specific IgA has been proposed to serve as a carrier to facilitate HAV transport to the
liver, thereby contributing to relapsing hepatitis A [23]. However, the significance of this
finding is questionable because circulating eHAV particles unlikely bind to IgA. As for
cholestatic hepatitis, it is usually marked by pruritus, fever, diarrhea, and weight loss,
along with high levels of bilirubin in patient serum [19]. Furthermore, HAV infection
is associated with multiple extrahepatic manifestations, including acute kidney injury,
autoimmune hemolytic anemia, aplastic anemia, and acute pancreatitis [11,20]. However,
these manifestations are rare.
3. Histologic Features of Hepatitis A in Humans
Microscopic changes in HAV infection have been extensively investigated by ana-
lyzing liver biopsy specimens collected from patients with hepatitis A. Acute hepatitis A
displays both degenerative and regenerative parenchymal changes, along with infiltrating
inflammatory cells [22]. However, the composition and proportion of inflammatory cells in
acute hepatitis A have not been well established. There is significant lobular disarray char-
acterized by swollen hepatocytes and hepatocyte necrosis, especially in the centrilobular
and midzonal areas. Kupffer cells in the sinusoids are activated and marked by hyper-
trophy and hyperplasia. The portal tracts are enlarged and infiltrated by lymphocytes,
neutrophils, eosinophils, and plasma cells [22,24]. Of note, varying degrees of portal fi-
brosis also occur in some cases [24]. The limiting plate of hepatocytes is disrupted due
to periportal changes. Notably, piecemeal necrosis marked by bridging hepatic necrosis,Viruses 2021, 13, 861 3 of 9
which is considered more common in chronic hepatitis, may also befall some patients with
acute hepatitis A [24,25].
The morphological features in patients with acute hepatitis A may vary depending on
age, gender, disease severity, and the time of liver tissue harvesting [25–28]. In patients with
fulminant hepatitis, massive hepatic necrosis takes over the liver [29]. The massive loss
of hepatocytes is usually accompanied by accumulation of inflammatory cells, including
T cells, NK cells, B cells, and both M1 and M2 macrophages [30]. In cholestatic hepatitis,
there is a varying degree of cholestasis characterized by bile thrombi, cholestatic rosettes,
and ductular transformation of hepatocytes [31]. Serology tests are usually employed to
determine the causes of acute viral hepatitis because patients with acute hepatitis A, B, C,
or E infection exhibit similar histologic features in liver tissues. Nevertheless, liver biopsy
remains the gold standard for assessing the severity of liver injury.
4. Mechanisms of Liver Injury during HAV Infection
Acute HAV infection has a stealthy nature. The virus replicates logarithmically in the
liver without any symptoms. Studies with experimentally infected chimpanzees revealed a
very limited induction of type I interferon-stimulated genes in the liver during the acute
phase [9]. This blunted type I IFN response is attributable to HAV protease-mediated cleav-
age of the mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing
adaptor-inducing interferon-β (TRIF) [32,33]. These two proteins are adaptors in the cyto-
plasmic viral RNA sensing pathways. HAV is sensitive to type I IFN in vitro, thus its ability
to limit IFN production in infected cells is likely critical for its survival. The long-term
persistence of intrahepatic viral RNA in HAV-infected chimpanzees may also be relevant
to relapsing hepatitis seen in up to 20% of patients following apparent resolution of acute
hepatitis [9].
The pathogenesis of hepatitis A and the mechanisms underlying hepatocellular injury
are incompletely understood. Since HAV does not directly cause cytopathic effects, it
is unlikely that viral cytolysis is responsible for liver injury during acute HAV infection.
Histological findings in liver biopsies obtained from patients and experimentally infected
animals demonstrate a strong temporal correlation between immune cell infiltration and
the disease, suggesting that cell-mediated mechanisms are critical for liver damage. While
virus-specific cytotoxic T lymphocytes (CTLs) have been generally thought to be a major
driver for HAV-associated immunopathology, emerging evidence suggests additional
mechanisms are involved. Below we summarize the current knowledge of the mechanisms
involved in liver injury caused by HAV infection.
4.1. Virus-Specific Cytotoxic T Lymphocytes (CTLs)
Virus-specific CTLs play a pivotal role in clearing virus-infected cells. However, they
may also cause tissue damage, thereby contributing to pathogenesis. Using peripheral
blood lymphocytes (PBLs) and autologous skin fibroblasts from patients with hepatitis A,
Vallbracht and colleagues demonstrated that PBLs could lyse HAV infected skin fibroblasts
in a human leukocyte antigen (HLA)-dependent manner [34,35]. The highest cytolytic
activity was found with PBLs collected during the early convalescent phase. However, it is
possible that a significant portion of the cytolytic cells accumulates in the liver at the climax
of the disease [34]. A follow-up study was conducted by the same group to confirm that
liver-derived CD8+ T cells were able to lyse HAV-infected skin fibroblasts [36]. These initial
studies provided the first evidence that virus-specific CTLs are involved in mediating liver
injury in acute hepatitis A (Figure 1A).Viruses 2021, 13, x FOR PEER REVIEW 4 of 9
Viruses 2021, 13, 861 4 of 9
[36]. These initial studies provided the first evidence that virus-specific CTLs are involved
in mediating liver injury in acute hepatitis A (Figure 1A).
Proposed mechanisms
Figure 1. Proposed mechanismsofofliver
liverinjury
injurymediated
mediatedbyby HAV.
HAV. (A)(A) During
During HAVHAV infection,
infection, the
the virus
virus activates+ CD8 + T cells, generating virus-specific+CD8+ T cells. Activated virus-specific +CD8+ T
activates CD8 T cells, generating virus-specific CD8 T cells. Activated virus-specific CD8 T cells
cellsdifferentiated
are are differentiated into effector
into effector cytotoxic
cytotoxic T lymphocytes
T lymphocytes that specifically
that specifically kill virus-infected
kill virus-infected cells, thus
cells, thus contributing to liver injury. (B) In patients with hepatitis A, high levels of IL-15 in the
contributing to liver injury. (B) In patients with hepatitis A, high levels of IL-15 in the serum activate
serum activate non-virus-specific CD8+ T cells, which are capable of lysing both infected and unin-
non-virus-specific CD8+ T cells, which are capable of lysing both infected and uninfected hepatocytes.
fected hepatocytes. (C) High levels of IL-18 have been detected in both macrophages and hepato-
(C) High
cytes levels of IL-18 have been detected
in IL-18BP-deficient-patients in both macrophages
with fulminant and hepatocytes
hepatitis A. Due in IL-18BP-deficient-
to lack of neutralizing activity
patients with fulminant
against IL-18, hepatitis
excessive and A. Due toIL-18
uncontrolled lack activates
of neutralizing activity
NK cells, which against IL-18, excessive
subsequently mediateand the
uncontrolled IL-18 activates
lysis of both infected NK cells,
and uninfected which subsequently
hepatocytes. mediate
(D) In patients withthe lysishepatitis
severe of both infected
A, HAVand
uninfected hepatocytes.
seems to activate (D) In
NKT cells in patients
a TIM-1 with severe manner.
dependent hepatitis HAV-infected
A, HAV seems cellsto activate NKT cyto-
had higher cells in a
toxic activity
TIM-1 in NKT
dependent cells carrying
manner. the longer
HAV-infected form
cells had of TIM-1
higher than in
cytotoxic NKT in
activity cells
NKTharboring the wild
cells carrying the
type TIM-1,
longer thereby
form of TIM-1contributing
than in NKTtocells
liver injury. Apoptosis
harboring of HAV-infected
the wild type TIM-1, thereby hepatocytes
contributing mediated
to liver
by MAVS-IRF3/IRF7-dependent
injury. Apoptosis of HAV-infectedsignaling
hepatocyteshas also been implicated
mediated in liver injury in a murine
by MAVS-IRF3/IRF7-dependent signaling
model of HAV [10].
has also been implicated in liver injury in a murine model of HAV [10].
In 2011,
In 2011, Schulte
Schulte et et al.
al. analyzed
analyzed CD8
CD8++ T cells in
T cells in patients
patients with
with acute,
acute, post-acute,
post-acute, and and
resolved HAV infection using class I multimers [37]. A broad CD8
resolved HAV infection using class I multimers [37]. A broad CD8 T cell response was++ T cell response was
found during
found during the
the acute
acute phase
phase ofof HAV infection. In
HAV infection. In the
the same
same year,
year, Yan
Yan et et al.
al. performed
performed aa
detailed analysis of T cell responses in chimpanzees experimentally infected withwith
detailed analysis of T cell responses in chimpanzees experimentally infected HAVHAV [38].
[38].
In In contrast
contrast to thetoSchutle
the Schutle
study,study,
the CD8 +
the CD8
T cellT response
+ cell responsewas was not found
not found to betotemporally
be tempo-
rally associated
associated with with
controlcontrol of infection
of infection or liver
or liver damage.
damage. Instead,
Instead, a adominant
dominantCD4 CD4 + +TT cell
cell
response was associated with virus clearance. This pattern was observed for T cells cells both
both
in blood and in liver [38]. Of note, transaminase
transaminase elevations
elevations werewere milder
milder in in the
the two
two HAV-
HAV-
infected chimpanzees
chimpanzees than in symptomatic human infections. Thus, it remains to de-
than in symptomatic human infections. Thus, it remains to be be
termined if CD8
determined if CD8 + T cells
+ T cells exertexert
a species-specific role or
a species-specific roleplay
or aplay
morea important
more important role inrole
severe
in
liver disease.
severe liver disease.
4.2. Liver Damage Mediated by Non-HAV-Specific Lymphocyte Activation
Accumulating evidence suggests that non-virus-specific lymphocytes also contribute
to liver injury in hepatitis A. As mentioned above, NK cells can lyse K562 cells and HAV-
infected cells in a non-specific manner in vitro [34]. Interestingly, PBLs from healthy donorsViruses 2021, 13, 861 5 of 9
never exposed to HAV exhibited greater lytic capability for HAV-infected BS-C-1 cells than
for uninfected cells [39]. The cellular composition involved in the lysis of HAV-infected
cells was determined to be positive for CD16+ and CD11b+ markers similar to those in NK
cells. These data indicated that cytotoxicity mediated by non-HAV-specific lymphocytes
such as NK cells likely contributed to the lysis of HAV-infected cells. It should be noted
that the effector cells in this study came from humans, while the target cells were derived
from the African Green Monkey kidney. Whether the results could reflect the mode of
action of PBLs against HAV-infected cells remains uncertain.
In addition to NK cells, non-HAV-specific CD8+ T cells have been shown to contribute
to liver injury [40]. In patients with hepatitis A, non-HAV-specific CD8+ T cells were
activated by high levels of IL-15, which was referred to as “bystander activation” [40].
These bystander-activated CD8+ T cells were capable of lysing Huh-7 cells. The cytolytic
activity of these CD8+ T cells could be blocked by antibodies against natural killer cell
activating receptors, such as NKG2D and NKp30. Of note, NKG2D ligands, including
MIC-A and MIC-B, were readily detected in HAV-infected and uninfected hepatocytes,
leading to the conclusion that both HAV-infected and uninfected hepatocytes may serve as
targets for non-HAV-specific CD8+ T cells [40] (Figure 1B). A more recent study by El Costa
et al. described similar results in hepatitis E virus (HEV)-infected-patients [41], suggesting
that the involvement of non-virus-specific CD8+ T cells in liver damage is probably more
common than previously appreciated.
4.3. Emerging Role of Intrinsic Apoptosis in HAV-Induced Liver Damage
In 2016, Hirai-Yuki et al. described the development of a murine model for HAV
infection [10]. HAV does not infect mice but replicates efficiently in mice deficient in the
type I IFN receptor (IFNAR1) or MAVS. Interestingly, IFNAR1-deficient mice developed
hepatitis after HAV infection, but MAVS-deficient mice did not. Typical histopathologic
lesions, including necrotic or apoptotic hepatocytes and inflammatory cell infiltration, were
observed in their liver tissue. However, these typical histopathologic lesions were not
observed in MAVS-deficient mice, although HAV replicated 10 times more efficiently in
the MAVS-deficient mice than in the IFNAR1-deficient mice. The results in IRF3- or IRF7-
deficient mice were similar. Notably, IFNAR1-deficient mice had low-level virus-specific
T cell responses, suggesting that the HAV-mediated liver injury in mice was related to
the MAVS-IRF3/IRF7 signaling pathway but not CTLs. Further supporting this notion,
depletion of T cells had little effect on HAV-induced ALT elevation in IFNAR-deficient mice.
However, the precise mechanism involving MAVS-mediated apoptosis in HAV-induced
liver injury remains unknown.
A separate study has shown that HAV can robustly infect Alb-uPA/SCID mice en-
grafted with human hepatocytes [42]. In this model, mice with severe combined immunod-
eficiency were engineered to express a urokinase-type plasminogen activator (uPA) under
the albumin promoter. The high-level expression of uPA resulted in progressive death of
murine hepatocytes, allowing their replacement with transplanted human hepatocytes.
The lack of adaptive immunity in these mice offered a unique advantage to assess HAV-
induced liver damage in the absence of adaptive immune responses, although ongoing
hepatotoxicity due to transgene expression might have been a confounding factor. Similar
to HAV-infected chimpanzees, a minimal type I and type II IFN response was detected in
the HAV-infected humanized mice. No definite evidence for hepatocyte damage related to
HAV infection was found in that study [42].
These studies with murine models have provided fresh insights into HAV infection
and pathogenesis. A surprising finding is that MAVS-mediated signaling not only deter-
mines the host species range of HAV but also results in intrinsic apoptosis of HAV-infected
hepatocytes. These data imply that cleavage of MAVS by HAV protease not only enhances
virus replication but may also help prevent/reduce liver damage. Whether these observa-
tions recapitulate the actual events of HAV infection in humans merits further study.Viruses 2021, 13, 861 6 of 9
4.4. Host Genetic Factors Involved in the Severity of Hepatitis A
Several host genetic factors have been shown to be linked to the severity of hepatitis
A. A patient with fulminant hepatitis presented with a 40 nt homozygous deletion in
the IL-18 binding protein (IL-18BP) gene generating three novel splice variants of IL-
18BP [30]. Intriguingly, all three isoforms of IL-18BP were prone to be degraded and
lacked neutralizing activity against IL-18, thus resulting in complete IL-18BP deficiency.
Patients with fulminant hepatitis A also had a high level of IL-18 in both macrophages and
hepatocytes. Consequently, both HAV-infected and uninfected hepatocytes were killed
by NK cells due to their activation by excessive and uncontrolled IL-18 production [30].
Therefore, uncontrolled IL-18–mediated cytotoxic activity against hepatocytes was likely
responsible for liver destruction in this particular patient [30] (Figure 1C).
Of note, IL-18 has been associated with susceptibility and disease progression of other
forms of viral hepatitis, including hepatitis B [43–45], hepatitis C [46–48], and hepatitis
E [41,49]. For example, the HBV X protein is able to upregulate IL-18 expression, which in
turn upregulates FasL expression in hepatoma cells [43]. Recombinant IL-18 inhibits HBV
replication in HBV transgenic mice by activating intrahepatic NK cells and NKT cells and
by inducing type I IFN production in infected liver [44]. IL-18, TNF, and IFN-γ alleles and
genotypes are also associated with susceptibility to chronic hepatitis B infection and severity
of liver injury [45]. In patients with hepatitis E, IL-18 activates non-HEV-specific effector
memory CD8+ T cells, thereby contributing to HEV pathogenesis [41]. IL-18 has also been
associated with HEV-induced renal disorder [49]. Thus, IL-18–mediated cytotoxic activity
appears to be a common contributing factor to liver injury in viral hepatitis, and the genetic
variations in IL-18/IL-18BP likely may have a significant impact on host susceptibility
and/or the severity of the disease.
An epidemiological study of children with severe hepatitis A identified a 6-amino-
acid insertion in T-cell immunoglobulin and mucin domain 1 (TIM-1) as a genetic factor
associated with the severity of hepatitis A [50]. TIM-1 was initially discovered as a cellular
receptor for HAV [51,52]. In patients with severe hepatitis A, NKT cells seem to be activated
by HAV in a TIM-1 dependent manner. A longer TIM-1 form displayed higher binding
affinities to HAV particles than the wild-type TIM-1. Correspondingly, NKT cells carrying
a longer TIM-1 form had a higher cytotoxic activity for HAV-infected cells [50]. Thus, the
authors proposed genetic variations in TIM-1 as a mechanism responsible for the severity
of HAV-induced hepatitis (Figure 1D). However, this model was questioned by Das and
colleagues, who demonstrated that TIM-1 is not essential for cellular entry of HAV [53].
Overall, both IL-18BP and TIM-1 genes are biologically plausible susceptibility genes for
hepatitis A, facilitating a risk evaluation for developing severe viral hepatitis in patients.
Although not discussed in detail, viral factors likely also play a role in modulating
the disease process. For example, the HAV protease processing intermediates 3ABC and
3CD cleave the multiple cellular factors MAVS and TRIF, respectively [32,33], thereby
dampening the innate response to infection. HAV also circulates in the bloodstream as
quasi-enveloped virions which are not recognized by circulating anti-HAV antibodies
but can activate plasmacytoid dendritic cells to produce type I interferons [54]. Finally,
genetic variations among HAV genotypes and strains could affect virus-host interactions
and disease pathogenesis, an area that so far has not been carefully studied.
Collectively, these new studies suggest that multiple components of the immune
system as well as genetic variations in certain host factors play roles in hepatocellular
damage during HAV infection. These mechanisms are not necessarily mutually exclusive,
and it is likely that either one or multiple mechanisms are involved in different disease
conditions. While many of these observations described above await validations by inde-
pendent studies, they nonetheless provide a framework for further investigation of the
mechanisms involved in HAV pathogenesis. More integrated approaches may be needed
for better understanding the mechanisms that drive liver damage in patients.Viruses 2021, 13, 861 7 of 9
5. Conclusions
Despite decades of research, the mechanisms of liver injury in hepatitis A remain
incompletely understood. While virus-specific CD8+ T cells have long been considered a
major cause of HAV-induced liver damage, new evidence suggests that additional mech-
anisms are involved. Other immune cells, including non-HAV-specific CD8+ T cells, NK
cells, and NKT cells, have been shown to contribute to liver damage. Additionally, intrinsic
apoptosis mediated by MAVS signaling appears to be responsible for hepatitis in a murine
model of HAV infection. Furthermore, genetic variations in both host and viral factors can
also influence the severity of hepatitis A. These mechanisms are not mutually exclusive
and can act either alone or in combination to drive liver damage in patients. It is almost
certain that with the ever-increasing knowledge and advances in technologies, additional
mechanisms will be discovered. Further elucidation of these mechanisms of HAV-induced
hepatocellular injury will shed new light on the pathogenesis of hepatitis A and facilitate
discovering novel therapeutic approaches.
Funding: This work was supported by the National Institute of Allergy and Infectious Diseases
(AI139511).
Conflicts of Interest: The authors declare no conflict of interest.
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